Abstract: Smoking is the leading risk factor for preventable morbidity and mortality, and smoking cessation remains the primary goal for population-based tobacco and cancer control. Many smokers lack resources to initiate and sustain a successful quit attempt. For the last decade we have been testing innovative approaches for delivery of pharmacotherapies that allow smokers to try evidence-based cessation medications and self- determine their goals and pace for cessation. Medication sampling is a brief, concrete, and easily understood exercise that often induces attitudinal shifts in favor of quitting smoking, and more importantly promotes quit attempts and actual cessation. Medication sampling is also favored by healthcare providers, augmenting their brief advice as per clinical guidelines. We have conducted three trials of nicotine replacement therapy (NRT) sampling (N=157, 849, 1245), all of which were remote, and some of which have been applied within medical settings. Each trial demonstrated increases in cessation behavior. Our prior work on NRT sampling creates a compelling question as to whether varenicline sampling would have similar, or potentially better, effects. Varenicline is inarguably the most effective single cessation medication available, superior to other monotherapy options. As a prescription medication, whether varenicline is suitable for sampling is unclear but worth testing empirically. On one hand, unstructured use, over a brief time, may not deliver sufficient pharmacologic benefit. Prescription delivery incurs its own barriers to widespread dissemination (which can be overcome). On the other hand, much like NRT sampling, it could provide a tangible cue to action that provides psychological engagement (motivation, confidence, autonomy) to sustain subsequent use and ultimately enhance cessation. A trial of varenicline sampling is not merely a routine extension of NRT trials, yet the significance is even more compelling given evidence of its unique benefits. We therefore propose a randomized clinical trial with primary aims to determine the 1) use, 2) consequences (on cessation), and 3) mechanisms of varenicline sampling. A demographically diverse sample of 648 smokers will be recruited across South Carolina and randomized (2:1:1) to receive I) a 4-week sample of varenicline, II) a 4-week supply of NRT, or III) nothing. Thus, our design is strengthened by both active and inactive comparison groups. Outcomes will be assessed through 6 months of follow-up. We employ innovations in mobile health technologies throughout to enhance methodological rigor, including remote biological verification of smoking behavior. If varenicline sampling were to show promise through this and future trials, this would offer great dissemination appeal to physicians, quitlines, etc in that, much like our NRT work, varenicline sampling could be a pragmatic strategy to engage more smokers in better treatments, sooner. Ultimately, the population impact of medication/varenicline sampling could be profound, offering a significant and measurable opportunity to lessen the impact of tobacco on public health and to reduce the risk, incidence and mortality of cancer.